Predisposition to clinical syndromes of vascular occlusion reflects the cumulative impact of xenobiotic and environmental insults, immunological susceptibility, an inflammatory response and genetic substrate. Injury may occur in many forms - an angioplasty catheter, a drugj a metabolic insult, an environmental toxin, or an infectious agent. Correspondingly, the genetic makeup of an individual may condition the vascular response by modulating metabolism or target expression for a drug or toxin or immunological response to invasion by a pathogen. Our incomplete understanding of this complex interaction is reflected by the modest repertoire of therapeutic options available to us to control or reverse this process. Rather than focus on a descriptive analysis of vascular injury, the present proposal takes a translational approach to defining mechanism in a domain replete with novel therapeutic targets - the intersection of the nicotinic acid / HM74A and PGD2 biosynthetic/ response systems. We avail of many novel models of gene deletion in mice, the discovery of new targets of drug action, such as HM74A and the DP2, arid the emergence of novel pharmacological probes to project and integrate our explorations of mechanism in mice into corresponding studies of the mechanism of vascular injury in humans. These basic and clinical studies in this highly integrated proposal will deploy a common approach - the use of common lipidomic and proteomic discovery tools, the common use of pharmacological probes and gene depleted mice, and common approaches to evocation of phenotypic responses in mice and humans. This will permit a truly translational approach using hypothesis based and unbiased methodologies to investigating the role of bioactive lipids in the response to vascular injury.